tbuckley/cabot-search huggingface dataset:
Macrolide therapy in Pseudomonas aeruginosa infections causes uL4 ribosomal protein mutations leading to high-level resistance
Authors: Lise Goltermann, Kasper Langebjerg Andersen, Helle Krogh Johansen, Søren Molin, Ruggero La Rosa
Journal: Clinical Microbiology and Infection (2022)

Pseudomonas aeruginosa colonizes the cystic fibrosis (CF) airways causing chronic bacterial lung infections. CF patients are routinely treated with macrolides, however, P. aeruginosa is considered insusceptible as consequence of inadequate susceptibility testing leaving resistance mechanism completely overlooked. Here, we investigated a new mechanism of macrolide resistance caused by ribosomal protein mutations.Investigating a longitudinal collection of 529 isolates from CF patients and analysing 5758 protein sequences from different sources, mutations in P. aeruginosa's ribosomal proteins connected to macrolide resistance were identified. Using a modified susceptibility testing protocol, isolates harbouring a mutated uL4 ribosomal protein were tested for resistance against macrolide antibiotics and macrolide-induced quorum sensing modulation. Proteome and ribosome profiling were applied to assess the impact of the mutations on the bacterial physiology.Five uL4 mutations were identified in isolates from different CF patients. Most mapped to the conserved loop region of uL4 and resulted in increased macrolide tolerance (>10-fold relative to wt strains). Greater concentrations (>10-fold) of macrolide antibiotic were needed to inhibit the growth, reduce swimming motility, and induce redox sensitivity of the uL4 mutants. 16 proteins involved in ribosome adaptation displayed altered expression possibly to compensate for the uL4 mutations, which changed the ribosome stoichiometry without negatively affecting bacterial physiology.Macrolide antibiotics should, therefore, be considered as active antimicrobial agents against P. aeruginosa and resistance development should be contemplated when patients are treated with prolonged courses of macrolides. Importantly, improved macrolide susceptibility testing is necessary for the detection of resistant bacteria.
Geographic, Occupational, and Sociodemographic Variations in Uptake of COVID-19 Booster Doses Among Fully Vaccinated US Adults, December 1, 2021, to January 10, 2022
Authors: Israel T. Agaku, Caleb Adeoye, Theodore G. Long
Journal: JAMA Network Open (2022)

COVID-19 booster vaccine can strengthen waning immunity and widen the range of immunity against new variants.To describe geographic, occupational, and sociodemographic variations in uptake of COVID-19 booster doses among fully vaccinated US adults.This cross-sectional survey study used data from the Household Pulse Survey conducted from December 1, 2021, to January 10, 2022. Household Pulse Survey is an online, probability-based survey conducted by the US Census Bureau and is designed to yield estimates nationally, by state, and across selected metropolitan areas.Receipt of a booster dose was defined as taking 2 or more doses of COVID-19 vaccines with the first one being the Johnson and Johnson (Janssen) vaccine, or taking 3 or more doses of any of the other COVID-19 vaccines. Weighted prevalence estimates (percentages) were computed overall and among subgroups. Adjusted prevalence ratios (APRs) were calculated in a multivariable Poisson regression model to explore correlates of receiving a booster dose among those fully vaccinated.A total of 135 821 adults completed the survey. Overall, 51.0% were female and 41.5% were aged 18 to 44 years (mean [SD] age, 48.07 [17.18] years). Of fully vaccinated adults, the percentage who reported being boosted was 48.5% (state-specific range, from 39.1% in Mississippi to 66.5% in Vermont). Nationally, the proportion of boosted adults was highest among non-Hispanic Asian individuals (54.1%); those aged 65 years or older (71.4%); those with a doctoral, professional, or master's degree (68.1%); those who were married with no children in the household (61.2%); those with annual household income of $200 000 or higher (69.3%); those enrolled in Medicare (70.9%); and those working in hospitals (60.5%) or in deathcare facilities (eg, funeral homes; 60.5%). Conversely, only one-third of those who ever received a diagnosis of COVID-19, were enrolled in Medicaid, working in pharmacies, with less than a high school education, and aged 18 to 24 years old were boosted. Multivariable analysis of pooled national data revealed that compared with those who did not work outside their home, the likelihood of being boosted was higher among adults working in hospitals (APR, 1.23; 95% CI, 1.17-1.30), ambulatory health care centers (APR, 1.16; 95% CI, 1.09-1.24), and social service settings (APR, 1.08; 95% CI, 1.01-1.15), whereas lower likelihood was seen among those working in food or beverage stores (APR, 0.85; 95% CI, 0.74-0.96) and the agriculture, forestry, fishing, or hunting industries (APR, 0.83; 95% CI, 0.72-0.97).These findings suggest continuing disparities in receipt of booster vaccine doses among US adults. Targeted efforts at populations with low uptake may be needed to improve booster vaccine coverage in the US.
Propionate and butyrate attenuate macrophage pyroptosis and osteoclastogenesis induced by CoCrMo alloy particles
Authors: Yang-Lin Wu, Chen-Hui Zhang, Yun Teng, Ying Pan, Nai-Cheng Liu, Pei-Xin Liu, Xu Zhu, Xin-Lin Su, Jun Lin
Journal: Military Medical Research (2022)

Abstract Background Wear particles-induced osteolysis is a major long-term complication after total joint arthroplasty. Up to now, there is no effective treatment for wear particles-induced osteolysis except for the revision surgery, which is a heavy psychological and economic burden to patients. A metabolite of gut microbiota, short chain fatty acids (SCFAs), has been reported to be beneficial for many chronic inflammatory diseases. This study aimed to investigate the therapeutic effect of SCFAs on osteolysis. Methods A model of inflammatory osteolysis was established by applying CoCrMo alloy particles to mouse calvarium. After two weeks of intervention, the anti-inflammatory effects of SCFAs on wear particle-induced osteolysis were evaluated by Micro-CT analysis and immunohistochemistry staining. In vitro study, lipopolysaccharide (LPS) primed bone marrow-derived macrophages (BMDMs) and Tohoku Hospital Pediatrics-1 (THP-1) macrophages were stimulated with CoCrMo particles to activate inflammasome in the presence of acetate (C2), propionate (C3), and butyrate (C4). Western blotting, Enzyme-linked immunosorbent assay, and immunofluorescence were used to detect the activation of NLRP3 inflammasome. The effects of SCFAs on osteoclasts were evaluate by qRT-PCR, Western blotting, immunofluorescence, and tartrate-resistant acid phosphatase (TRAP) staining. Additionally, histone deacetylase (HDAC) inhibitors, agonists of GPR41, GPR43, and GPR109A were applied to confirm the underlying mechanism of SCFAs on the inflammasome activation of macrophages and osteoclastogenesis. Results C3 and C4 but not C2 could alleviate wear particles-induced osteolysis with fewer bone erosion pits ( P &lt; 0.001), higher level of bone volume to tissue volume (BV/TV, P &lt; 0.001), bone mineral density (BMD, P &lt; 0.001), and a lower total porosity ( P &lt; 0.001). C3 and C4 prevented CoCrMo alloy particles-induced ASC speck formation and nucleation-induced oligomerization, suppressing the cleavage of caspase-1 ( P &lt; 0.05) and IL-1β ( P &lt; 0.05) stimulated by CoCrMo alloy particles. C3 and C4 also inhibited the generation of Gasdermin D-N-terminal fragment (GSDMD-NT) to regulate pyroptosis. Besides, C3 and C4 have a negative impact on osteoclast differentiation ( P &lt; 0.05) and its function ( P &lt; 0.05), affecting the podosome arrangement and morphologically normal podosome belts formation. Conclusion Our work showed that C3 and C4 are qualified candidates for the treatment of wear particle-induced osteolysis.
The emerging role of furin in neurodegenerative and neuropsychiatric diseases
Authors: Yi Zhang, Xiaoqin Gao, Xue Bai, Shanshan Yao, Yan-Zhong Chang, Guofen Gao
Journal: Translational Neurodegeneration (2022)

Furin is an important mammalian proprotein convertase that catalyzes the proteolytic maturation of a variety of prohormones and proproteins in the secretory pathway. In the brain, the substrates of furin include the proproteins of growth factors, receptors and enzymes. Emerging evidence, such as reduced FURIN mRNA expression in the brains of Alzheimer's disease patients or schizophrenia patients, has implicated a crucial role of furin in the pathophysiology of neurodegenerative and neuropsychiatric diseases. Currently, compared to cancer and infectious diseases, the aberrant expression of furin and its pharmaceutical potentials in neurological diseases remain poorly understood. In this article, we provide an overview on the physiological roles of furin and its substrates in the brain, summarize the deregulation of furin expression and its effects in neurodegenerative and neuropsychiatric disorders, and discuss the implications and current approaches that target furin for therapeutic interventions. This review may expedite future studies to clarify the molecular mechanisms of furin deregulation and involvement in the pathogenesis of neurodegenerative and neuropsychiatric diseases, and to develop new diagnosis and treatment strategies for these diseases.
Augmenting neurogenesis rescues memory impairments in Alzheimer’s disease by restoring the memory-storing neurons
Authors: Rachana Mishra, Trongha Phan, Pavan Kumar, Zachery Morrissey, Muskan Gupta, Carolyn Hollands, Aashutosh Shetti, Kyra Lauren Lopez, Mark Maienschein-Cline, Hoonkyo Suh, Rene Hen, Orly Lazarov
Journal: The Journal of Experimental Medicine (2022)

Hippocampal neurogenesis is impaired in Alzheimer’s disease (AD) patients and familial Alzheimer’s disease (FAD) mouse models. However, it is unknown whether new neurons play a causative role in memory deficits. Here, we show that immature neurons were actively recruited into the engram following a hippocampus-dependent task. However, their recruitment is severely deficient in FAD. Recruited immature neurons exhibited compromised spine density and altered transcript profile. Targeted augmentation of neurogenesis in FAD mice restored the number of new neurons in the engram, the dendritic spine density, and the transcription signature of both immature and mature neurons, ultimately leading to the rescue of memory. Chemogenetic inactivation of immature neurons following enhanced neurogenesis in AD, reversed mouse performance, and diminished memory. Notably, AD-linked App, ApoE, and Adam10 were of the top differentially expressed genes in the engram. Collectively, these observations suggest that defective neurogenesis contributes to memory failure in AD.
Unbiased discovery of autoantibodies associated with severe COVID-19 via genome-scale self-assembled DNA-barcoded protein libraries
Authors: Joel J. Credle, Jonathan Gunn, Puwanat Sangkhapreecha, Daniel R. Monaco, Xuwen Alice Zheng, Hung-Ji Tsai, Azaan Wilbon, William R. Morgenlander, Andre Rastegar, Yi Dong, Sahana Jayaraman, Lorenzo Tosi, Biju Parekkadan, Alan N. Baer, Mario Roederer, Evan M. Bloch, Aaron A. R. Tobian, Israel Zyskind, Jonathan I. Silverberg, Avi Z. Rosenberg, Andrea L. Cox, Tom Lloyd, Andrew L. Mammen, H. Benjamin Larman
Journal: Nature Biomedical Engineering (2022)
First-in-human Intravesical Delivery of Pembrolizumab Identifies Immune Activation in Bladder Cancer Unresponsive to Bacillus Calmette-Guérin
Authors: Khyati Meghani, Lauren Folgosa Cooley, Bonnie Choy, Masha Kocherginsky, Suchitra Swaminathan, Sabah S. Munir, Robert S. Svatek, Timothy Kuzel, Joshua J. Meeks
Journal: European Urology (2022)

Intravenous immune checkpoint inhibition is an effective anticancer strategy for bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) but may be associated with greater systemic toxicity compared with localized therapies.We assessed the safety and antitumor activity of intravesical pembrolizumab combined with BCG.A 3 + 3 phase 1 trial of pembrolizumab + BCG was conducted in patients with BCG-unresponsive NMIBC (NCT02808143).Pembrolizumab was given intravesically (1-5 mg/kg for 2 h) beginning 2 weeks prior to BCG induction until recurrence. Urine profiling during treatment and spatial transcriptomic profiling of pre- and post-treatment tumors were conducted to identify biomarkers that correlated with response.Safety and tolerability of immune checkpoint inhibition were assessed, and Kaplan-Meier survival analysis was performed.Nine patients completed therapy. Median follow-up was 35 months for five patients still alive at the end of the trial. The trial was closed due to the COVID-19 pandemic. Grade 1-2 urinary symptoms were common. The maximum tolerated dose was not reached; however, one dose-limiting toxicity was reported (grade 2 diarrhea) in the only patient who reached 52 weeks without recurrence. One death occurred from myasthenia gravis that was deemed potentially related to treatment. The 6-mo and 1-yr recurrence-free rates were 67% (95% confidence interval [CI]: 42-100%) and 22% (95% CI: 6.5-75%), respectively. Pembrolizumab was detected in the urine and not in blood. CD4+ T cells were significantly increased in the urine after treatment, and a transcriptomic analysis identified decreased expression of T-cell exhaustion markers in late recurrences.We demonstrate that intravesical pembrolizumab is safe, feasible, and capable of eliciting strong immune responses in a clinical setting and should be investigated further.Direct application of pembrolizumab to the bladder is a promising alternative for non-muscle-invasive bladder cancer unresponsive to Bacillus Calmette-Guérin and should be investigated further.
Whiplash Injury and Brain Damage
Authors: Ayub K. Ommaya
Journal: JAMA (1968)

Experimental whiplash injury in rhesus monkeys has demonstrated that experimental cerebral concussion, as well as gross hemorrhages and contusions over the surface of the brain and upper cervical cord, can be produced by rotational displacement of the head on the neck alone, without significant direct head impact. These experimental observations have been studied in the light of published reports of cerebral concussion and other evidence for central nervous system involvement after whiplash injury in man.
Advanced Hydrogel systems for mandibular reconstruction
Authors: Jiaxin Guo, Hao Yao, Xu Li, Liang Chang, Zixuan Wang, Wangyong Zhu, Yuxiong Su, Ling Qin, Jiankun Xu
Journal: Bioactive Materials (2022)

Mandibular defect becomes a prevalent maxillofacial disease resulting in mandibular dysfunctions and huge psychological burdens to the patients. Considering the routine presence of oral contaminations and aesthetic restoration of facial structures, the current clinical treatments are however limited, incapable to reconstruct the structural integrity and regeneration, spurring the need for cost-effective mandibular tissue engineering. Hydrogel systems possess great merit for mandibular reconstruction with precise involvement of cells and bioactive factors. In this review, current clinical treatments and distinct mode(s) of mandible formation and pathological resorption are summarized, followed by a review of hydrogel-related mandibular tissue engineering, and an update on the advanced fabrication of hydrogels with improved mechanical property, antibacterial ability, injectable form, and 3D bioprinted hydrogel constructs. The exploration of advanced hydrogel systems will lay down a solid foundation for a bright future with more biocompatible, effective, and personalized treatment in mandibular reconstruction.
Immuno-genomic profiling of biopsy specimens predicts neoadjuvant chemotherapy response in esophageal squamous cell carcinoma
Authors: Shota Sasagawa, Hiroaki Kato, Koji Nagaoka, Changbo Sun, Motohiro Imano, Takao Sato, Todd A. Johnson, Masashi Fujita, Kazuhiro Maejima, Yuki Okawa, Kazuhiro Kakimi, Takushi Yasuda, Hidewaki Nakagawa
Journal: Cell Reports Medicine (2022)

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and is primarily treated with platinum-based neoadjuvant chemotherapy (NAC). Some ESCCs respond well to NAC. However, biomarkers to predict NAC sensitivity and their response mechanism in ESCC remain unclear. We perform whole-genome sequencing and RNA sequencing analysis of 141 ESCC biopsy specimens before NAC treatment to generate a machine-learning-based diagnostic model to predict NAC reactivity in ESCC and analyzed the association between immunogenomic features and NAC response. Neutrophil infiltration may play an important role in ESCC response to NAC. We also demonstrate that specific copy-number alterations and copy-number signatures in the ESCC genome are significantly associated with NAC response. The interactions between the tumor genome and immune features of ESCC are likely to be a good indicator of therapeutic capability and a therapeutic target for ESCC, and machine learning prediction for NAC response is useful.
Feasibility of anomaly score detected with deep learning in irradiated breast cancer patients with reconstruction
Authors: Dong-Yun Kim, Soo Jin Lee, Eun-Kyu Kim, Eunyoung Kang, Chan Yeong Heo, Jae Hoon Jeong, Yujin Myung, In Ah Kim, Bum-Sup Jang
Journal: npj Digital Medicine (2022)

Abstract The aim of this study is to evaluate cosmetic outcomes of the reconstructed breast in breast cancer patients, using anomaly score (AS) detected by generative adversarial network (GAN) deep learning algorithm. A total of 251 normal breast images from patients who underwent breast-conserving surgery were used for training anomaly GAN network. GAN-based anomaly detection was used to calculate abnormalities as an AS, followed by standardization by using z-score. Then, we reviewed 61 breast cancer patients who underwent mastectomy followed by reconstruction with autologous tissue or tissue expander. All patients were treated with adjuvant radiation therapy (RT) after reconstruction and computed tomography (CT) was performed at three-time points with a regular follow-up; before RT (Pre-RT), one year after RT (Post-1Y), and two years after RT (Post-2Y). Compared to Pre-RT, Post-1Y and Post-2Y demonstrated higher AS, indicating more abnormal cosmetic outcomes (Pre-RT vs. Post-1Y, P = 0.015 and Pre-RT vs. Post-2Y, P = 0.011). Pre-RT AS was higher in patients having major breast complications ( P = 0.016). Patients with autologous reconstruction showed lower AS than those with tissue expander both at Pre-RT (2.00 vs. 4.19, P = 0.008) and Post-2Y (2.89 vs. 5.00, P = 0.010). Linear mixed effect model revealed that days after baseline were associated with increased AS ( P = 0.007). Also, tissue expander was associated with steeper rise of AS, compared to autologous tissue ( P = 0.015). Fractionation regimen was not associated with the change of AS ( P = 0.389). AS detected by deep learning might be feasible in predicting cosmetic outcomes of RT-treated patients with breast reconstruction. AS should be validated in prospective studies.
Essentials of Physiological Chemistry
Journal: JAMA (1953)

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GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice
Authors: Carmelo Quarta, Kerstin Stemmer, Aaron Novikoff, Bin Yang, Felix Klingelhuber, Alex Harger, Mostafa Bakhti, Aimee Bastidas-Ponce, Eric Baugé, Jonathan E. Campbell, Megan Capozzi, Christoffer Clemmensen, Gustav Collden, Perla Cota, Jon Douros, Daniel J. Drucker, Barent DuBois, Annette Feuchtinger, Cristina Garcia-Caceres, Gerald Grandl, Nathalie Hennuyer, Stephan Herzig, Susanna M. Hofmann, Patrick J. Knerr, Konxhe Kulaj, Fanny Lalloyer, Heiko Lickert, Arek Liskiewicz, Daniela Liskiewicz, Gandhari Maity, Diego Perez-Tilve, Sneha Prakash, Miguel A. Sanchez-Garrido, Qian Zhang, Bart Staels, Natalie Krahmer, Richard D. DiMarchi, Matthias H. Tschöp, Brian Finan, Timo D. Müller
Journal: Nature Metabolism (2022)

Dual agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPARɑ/ɣ) have beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to potential adverse effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPARɑ/ɣ dual-agonist tesaglitazar to a GLP-1 receptor agonist (GLP-1RA) to allow for GLP-1R-dependent cellular delivery of tesaglitazar. GLP-1RA/tesaglitazar does not differ from the pharmacokinetically matched GLP-1RA in GLP-1R signalling, but shows GLP-1R-dependent PPARɣ-retinoic acid receptor heterodimerization and enhanced improvements of body weight, food intake and glucose metabolism relative to the GLP-1RA or tesaglitazar alone in obese male mice. The conjugate fails to affect body weight and glucose metabolism in GLP-1R knockout mice and shows preserved effects in obese mice at subthreshold doses for the GLP-1RA and tesaglitazar. Liquid chromatography-mass spectrometry-based proteomics identified PPAR regulated proteins in the hypothalamus that are acutely upregulated by GLP-1RA/tesaglitazar. Our data show that GLP-1RA/tesaglitazar improves glucose control with superior efficacy to the GLP-1RA or tesaglitazar alone and suggest that this conjugate might hold therapeutic value to acutely treat hyperglycaemia and insulin resistance.
Antithrombotic Therapy for Symptomatic Peripheral Arterial Disease: A Systematic Review and Network Meta-Analysis
Authors: Loes H. Willems, Dominique P. M. S. M. Maas, Kees Kramers, Michel M. P. J. Reijnen, Niels P. Riksen, Hugo Ten Cate, Rozemarijn J. van der Vijver-Coppen, Gert J. de Borst, Barend M. E. Mees, Clark J. Zeebregts, Gerjon Hannink, Michiel C. Warlé
Journal: Drugs (2022)

High-quality evidence from trials directly comparing single antiplatelet therapies in symptomatic peripheral arterial disease (PAD) to dual antiplatelet therapies or acetylsalicylic acid (ASA) plus low-dose rivaroxaban is lacking. Therefore, we conducted a network meta-analysis on the effectiveness of all antithrombotic regimens studied in PAD.
The Staging of Hodgkin's Disease
Authors: Joseph Smith
Journal: JAMA (1973)

Thirty-three patients with Hodgkin's disease had a preoperative staging evaluation and then a laparotomy. There were three major postoperative complications. Of 19 preoperative stage I and IIcases, two became stage III and none became stage IV. Both of the cases which became stage III would have received adequate treatment by extended field and splenic radiotherapy. The data suggest that in cases initially in stage I or II with disease above the diaphragm, laparotomy is not necessary if extended field and splenic irradiation is administered. Those patients whose disease is initially staged as III or IV should have a laparotomy.